<p>As part of the 3D printing scaffolding process, chemical cross-linking can be employed as a step in the 3D printing process (post-process) to improve its properties. In this study, the impact of two chemical cross-linking agents (EDC/NHS and genipin) on the physical, chemical, and mechanical properties of scaffolds printed using a collagen, polycaprolactone, and chitosan ink (65% Col/30% PCL/5% Chi) was investigated. FTIR demonstrated that neither of two chemical cross-linking agents affected chemical composition of proposed scaffolds. The swelling ability showed that the proposed cross-linking post-process enhanced the scaffolds' water absorption capacity, while the contact angle measurements indicated an improvement in their hydrophilic properties after cross-linking. On the other hand, EDC/NHS cross-linked scaffolds demonstrated superior thermal stability and mechanical behaviors more adequate for skin application. SEM revealed that EDC/NHS cross-linked scaffolds have a more fibrous surface texture and anisotropic behavior compared to genipin cross-linked scaffolds. The proliferations assays with gingival fibroblast (HGF) showed that scaffolds cross-linked with EDC/NHS had more proliferation than scaffolds crosslinked with genipin at the different cell culture time. The results of this study indicate that EDC/NHS crosslinking is a more effective method to improve the properties of 3D-printed Col/PCL/Chi scaffolds than genipin and for that reason EDC/NHS is a good choice to be used as a printing post-process to improve the physical, chemical, and mechanical properties of 3D-printed Col/PCL/Chi scaffolds with possible applications for skin regeneration.</p>